Vitamin D3 Metabolism and Its Role in Temporomandibular Joint Osteoarthritis and Autoimmune Thyroid Diseases

The aim of this review was to present the metabolism of vitamin D3, as well as to discuss the role of vitamin D3 in bone metabolism, temporomandibular joint osteoarthritis (TMJ OA), and autoimmune thyroid diseases (AITD) on the basis of the literature. Vitamin D3 plays a significant role in human health, as it affects the calcium-phosphate balance and regulates the bone metabolism. Calcitriol impresses the pleiotropic effect on human biology and metabolism. Its modulative function upon the immune system is based on the reduction of Th1 cell activity and increased immunotolerance. Vitamin D3 deficiency may lead to an imbalance in the relationship between Th1/Th17 and Th2, Th17/Th reg, and is considered by some authors as one of the possible backgrounds of autoimmune thyroid diseases (AITD), e.g., Hashimoto’s thyroiditis or Graves’ disease. Moreover, vitamin D3, through its direct and indirect influence on bones and joints, may also play an important role in the development and progression of degenerative joint diseases, including temporomandibular joint osteoarthritis. Further randomized, double blind studies are needed to unequivocally confirm the relationship between vitamin D3 and abovementioned diseases and to answer the question concerning whether vitamin D3 supplementation may be used in the prevention and/or treatment of either AITD or OA diseases.


Introduction
Calcium ions play a significant role in several vital processes in the human body, including blood clotting, muscle contraction, proper nerve activity, and bone turnover, as well as affect the cell membrane activity [1]. The physiologic concentration of calcium within serum depends on calcium absorption from the gastrointestinal tract, the intensity of calcification processes, and finally on the urine calcium excretion. Calcium homeostasis is controlled by three hormones: parathyroid hormone (PTH), calcitonin, and 1,25-dihydroxycholecalciferol, also known as 1,25-dihydroxyvitamin D 3 [1].
Vitamin D 3 is a fat-soluble steroid prohormone, which is well-known in medicine for over 100 years, especially for its invaluable role in rickets prevention [2], maintenance of calcium-phosphate balance, and finally due to its role in bone metabolism [3]. The disorders of calcium metabolism are most commonly related to the imbalance of osteoblasts and osteoclast activity, leading to osteopenia and osteoporosis [4][5][6]. Moreover, deficits of vitamin D 3 have also been found to affect the skin issues, autoimmune disorders, cancers, cardiovascular, and metabolic diseases [7,8]. In addition, 1,25-dihydroxyvitamin D 3 increases the concentration of calcium ions within the extracellular fluid by increasing the renal calcium and phosphate reabsorption, by increasing the intestinal calcium absorption, as well as by increasing bone resorption [9].
Vitamin D 3 is in great interest of many different specialties, including among others endocrinology, and dentistry. Low levels of vitamin D 3 have been linked with the presence Vitamin D3 is a pro-hormone, but it was initially categorized as a vitamin, because it can be absorbed from dietary products, mainly oily fish, fish oil, dairy products, meat, eggs and some mushrooms. Nevertheless, the main source of vitamin D3 in humans is biosynthesis from 7-dehydrocholesterol in the course of photochemical reaction within the human skin [28].
Cholecalciferol is a prohormone that having been biosynthesized within the skin must undergo further transformations to become a biologically active hormone. Cholecalciferol becomes hydroxylated in the position of C25 by the enzyme 25-hydroxylase (CYP2R1, cytochrome P450 family) in the endoplasmic reticulum of the hepatocytes, or by CYP27A1 in the hepatic mitochondria. The product of the above described reaction is 25-hydroxyvitamin D3 (25(OH)D3) [29,30]. Enzymatic activity is regulated by negative feedback, where increased blood serum concentration of 25(OH)D3 decreases hydroxylation of vitamin D3. An excessive amount of vitamin D3 is stored in liver, muscles, or adipocytes [31]. 25-hydroxyvitamin-D3 is the major form of vitamin D3 circulating in the bloodstream with a long half-life time of 2-3 weeks. Therefore, measurement of blood serum concentration of 25(OH)D3 is a golden standard in the assessment of vitamin D3 deficits in humans [27]. 25(OH)D3 is subsequently bound to the vitamin-D3 binding protein (DBP) and transported to the kidneys. Human DBP, also called group-specific component (GC), is a protein composed of 458 amino acids [32]. Most of the total plasma 25(OH)D3 is transported being bound to DBP, and only less than 10% is carried by the albumins [33]. The affinity of DBP is 10-100 times greater for 25(OH)D3 than to 1,25(OH)2D3 [34].
Subsequently, mainly in renal mitochondria, 25(OH)D3 becomes hydroxylated at the C1α position by the 1α-hydroxylase (CYP27B1) to the biologically active hormone 1,25(OH)2D3 (calcitriol). Enzyme CYP27B1 has also been found in other tissues, including skin, placenta, and many cells of the immune system that are able to produce calcitriol locally on tissue demand [35]. Renal 1α-hydroxylase activity is directly controlled (stimulated) by PTH, and inhibited by calcium, phosphates, or fibroblast growth factor 23 . Contrary to this, local biosynthesis of 1,25(OH)2D3 in peripheral tissues (e.g., by monocytes and macrophages) is controlled among others by the activity of the immune system, implying auto-and paracrine properties of vitamin D (apart from calcium and phosphate metabolism) [36]. Vitamin D 3 is a pro-hormone, but it was initially categorized as a vitamin, because it can be absorbed from dietary products, mainly oily fish, fish oil, dairy products, meat, eggs and some mushrooms. Nevertheless, the main source of vitamin D 3 in humans is biosynthesis from 7-dehydrocholesterol in the course of photochemical reaction within the human skin [28].
Cholecalciferol is a prohormone that having been biosynthesized within the skin must undergo further transformations to become a biologically active hormone. Cholecalciferol becomes hydroxylated in the position of C25 by the enzyme 25-hydroxylase (CYP2R1, cytochrome P450 family) in the endoplasmic reticulum of the hepatocytes, or by CYP27A1 in the hepatic mitochondria. The product of the above described reaction is 25-hydroxyvitamin D 3 (25(OH)D 3 ) [29,30]. Enzymatic activity is regulated by negative feedback, where increased blood serum concentration of 25(OH)D 3 decreases hydroxylation of vitamin D 3 . An excessive amount of vitamin D 3 is stored in liver, muscles, or adipocytes [31]. 25-hydroxyvitamin-D 3 is the major form of vitamin D 3 circulating in the bloodstream with a long half-life time of 2-3 weeks. Therefore, measurement of blood serum concentration of 25(OH)D 3 is a golden standard in the assessment of vitamin D3 deficits in humans [27]. 25(OH)D 3 is subsequently bound to the vitamin-D 3 binding protein (DBP) and transported to the kidneys. Human DBP, also called group-specific component (GC), is a protein composed of 458 amino acids [32]. Most of the total plasma 25(OH)D 3 is transported being bound to DBP, and only less than 10% is carried by the albumins [33]. The affinity of DBP is 10-100 times greater for 25(OH)D 3 than to 1,25(OH) 2 D 3 [34].
Subsequently, mainly in renal mitochondria, 25(OH)D 3 becomes hydroxylated at the C1α position by the 1α-hydroxylase (CYP27B1) to the biologically active hormone 1,25(OH) 2 D 3 (calcitriol). Enzyme CYP27B1 has also been found in other tissues, including skin, placenta, and many cells of the immune system that are able to produce calcitriol locally on tissue demand [35]. Renal 1α-hydroxylase activity is directly controlled (stimulated) by PTH, and inhibited by calcium, phosphates, or fibroblast growth factor 23 (FGF-23). Contrary to this, local biosynthesis of 1,25(OH) 2 D 3 in peripheral tissues (e.g., by monocytes and macrophages) is controlled among others by the activity of the immune system, implying auto-and paracrine properties of vitamin D (apart from calcium and phosphate metabolism) [36].

Vitamin D3 Receptor and Mechanisms of Action
Two different mechanisms describing biological activity of vitamin D3 have been discovered, namely: genomic (via vitamin D receptor) and non-genomic (pleiotropic effect) [37].
Vitamin D3 enters the cytoplasm of the cell either as a free molecule or in the process of endocytosis supported by the LDL receptor-related protein 2 (LRP2)-cubilin (CUBN) complex [38]. Within the genomic pathway, vitamin D3 binds to the vitamin-D receptor (VDR) and therefore forms the vitamin D3-VDR complex. VDR belongs to the steroid hormone nuclear receptors family, which includes: glucocorticoid, mineralocorticoid, estrogen, androgen, progesterone receptors [38]. VDR is a gene transcription factor consisting of three domains: C-terminal ligand-bind domain, N-terminal DNA-binding domain with two zinc fingers to link up with accessible DNA sites, and a clip area that binds these two together [39,40]. The VDR is activated by binding to calcitriol (1,25(OH)2D3) and subsequently transforms into heterodimer with retinoid receptor X (RXR). The calcitriol-

Vitamin D 3 Receptor and Mechanisms of Action
Two different mechanisms describing biological activity of vitamin D 3 have been discovered, namely: genomic (via vitamin D receptor) and non-genomic (pleiotropic effect) [37].
Vitamin D 3 enters the cytoplasm of the cell either as a free molecule or in the process of endocytosis supported by the LDL receptor-related protein 2 (LRP2)-cubilin (CUBN) complex [38]. Within the genomic pathway, vitamin D3 binds to the vitamin-D receptor (VDR) and therefore forms the vitamin D3-VDR complex. VDR belongs to the steroid hormone nuclear receptors family, which includes: glucocorticoid, mineralocorticoid, estrogen, androgen, progesterone receptors [38]. VDR is a gene transcription factor consisting of three domains: C-terminal ligand-bind domain, N-terminal DNA-binding domain with two zinc fingers to link up with accessible DNA sites, and a clip area that binds these two together [39,40]. The VDR is activated by binding to calcitriol (1,25(OH) 2 D 3 ) and subsequently transforms into heterodimer with retinoid receptor X (RXR). The calcitriol-VDR-RXR complex binds to the specific gene promoter region of the DNA and therefore is able to either promote or inhibit the RNA polymerase II specific VDR-dependent genes [10]. Figure 3 presents the classic vitamin D 3 pathway on the basis of the literature [38].
VDR-RXR complex binds to the specific gene promoter region of the DNA and therefore is able to either promote or inhibit the RNA polymerase II specific VDR-dependent genes [10]. Figure 3 presents the classic vitamin D3 pathway on the basis of the literature [38]. 1,25(OH)2D3 regulates more than 1000 genes in more than 200 tissues and cells within the human body [38,41]. In an in vitro experiment, when a cell culture model was exposed to a calcitriol concentration higher than physiologic (10-100 nM 1,25(OH)2D3), it took few hours to observe first biological effects [42].
The so-called non-genomic mechanism of action takes seconds to minutes and does not depend on VDR activation, nor gene transcription [38]. 1,25(OH)2D3 can cause calcium influx in cells. In a study from 1990 on osteogenic sarcoma cell line ROS 17/2.8, there was observed a rapid calcium inflow in cell culture treated with 1,25(OH)2D3 [43]. Another example of rapid, hormonally stimulated transport of calcium by enterocytes is called transcalathia [44]. Furthermore, calcitriol enables rapid (1-10 min) tissue uptake of calcium in myocardial chicken cells. Hormonal stimulations lead to microsomal membrane protein phosphorylation and activation of cyclic-AMP pathway [45]. According to the free hormone hypothesis, vitamin D3 is a hydrophobic molecule, which is able to naturally enter the phospholipid membrane, thus probably no membrane receptor or specific protein is needed in transmembrane transport [46]. Therefore, various pathways are known to be regulated by vitamin D3. This creates a possibility for clinical practice to individualize cell-specified therapy by vitamin D3 and its analogues. 1,25(OH) 2 D 3 regulates more than 1000 genes in more than 200 tissues and cells within the human body [38,41]. In an in vitro experiment, when a cell culture model was exposed to a calcitriol concentration higher than physiologic (10-100 nM 1,25(OH) 2 D 3 ), it took few hours to observe first biological effects [42].
The so-called non-genomic mechanism of action takes seconds to minutes and does not depend on VDR activation, nor gene transcription [38]. 1,25(OH) 2 D 3 can cause calcium influx in cells. In a study from 1990 on osteogenic sarcoma cell line ROS 17/2.8, there was observed a rapid calcium inflow in cell culture treated with 1,25(OH) 2 D 3 [43]. Another example of rapid, hormonally stimulated transport of calcium by enterocytes is called transcalathia [44]. Furthermore, calcitriol enables rapid (1-10 min) tissue uptake of calcium in myocardial chicken cells. Hormonal stimulations lead to microsomal membrane protein phosphorylation and activation of cyclic-AMP pathway [45]. According to the free hormone hypothesis, vitamin D 3 is a hydrophobic molecule, which is able to naturally enter the phospholipid membrane, thus probably no membrane receptor or specific protein is needed in transmembrane transport [46]. Therefore, various pathways are known to be regulated by vitamin D 3 . This creates a possibility for clinical practice to individualize cell-specified therapy by vitamin D 3 and its analogues.

Vitamin D 3 and Immune System
Various immune cells express VDR, thus active vitamin D 3 plays a vital role in human immune system. The VDR is present in both B and T lymphocytes, as well as in antigen presenting cells (APC), including monocytes, macrophages and dendritic cells [47]. Interestingly, leukocytes, especially APCs, are also able to activate circulating 25(OH)D 3 to 1,25(OH) 2 D 3 through 1α -hydroxylase (CYP27B1) [48]. Biological effects of calcitriol on leukocytes affect: cell proliferation, differentiation, maturation, and apoptosis (programmed cell death). Furthermore, 1,25(OH) 2 D 3 affects the immunological balance between cellmediated (Th1) and humoral (Th2) response [49].
The antigen presenting cells specialize in presenting hostile antigen to T lymphocytes. Dendritic cells (DCs) are the most common and powerful APCs. The presentation of antigen affects through major histocompatibility complex protein (MHC). The DCs play crucial role in immunization and immunotolerance balance, which is strongly associated with cell maturation [50]. Immature dendritic cells stimulate regulatory (suppressor) T cell proliferation, whereas mature DCs, capable of antigen presenting, promote naive T cells to differentiate to Th1 lymphocytes and enhance pro-inflammatory response.
The T cell population differentiates into T helpers (Th, CD4+) and cytotoxic T cells (Tc, CD8+). Within the group of Th cells, there can be distinguished, among others, Th1, Th2, and Th17 cells. Maturation from naive T CD4+ to Th1 cells involves presenting the antigen by APCs in lymph nodes. VDR is present within the naive T cells, thus the vitamin D 3 can directly influence T cell responses. Furthermore, calcitriol affects the differentiation of the T cell subclasses by inhibiting naive CD4+ T cells proliferation to Th1 cells and promoting maturation of Th2 cells. Moreover, vitamin D 3 suppresses pro-inflammatory cytokine production (IL-2, INF-γ) by Th1 cells and simultaneously increases the production of antiinflammatory cytokines by Th2 cells (IL-4, IL-5, IL-10) [53]. Therefore, vitamin D 3 controls the Th1/Th2 immune balance and limits the Th1-induced destructive impact on tissues. Immune cells producing IL-17 (Th17) represent a quite new T cell subclass. The cytokine profile of Th17 cells (TNF-α, IL-6, IL-17, IL-21, IL-22) indicates that Th17 cells stimulate pro-inflammatory response in many diseases [54,55]. Probably, Th17 cells play a significant role in autoimmune diseases through pro-inflammatory cytokines, as there are many tissues that express receptors for IL-17 and IL-22. There have been published studies that provide the evidence of suppressive action of vitamin D 3 on Th17 cells, leading to the decreased production of IL-17 and other cytokines (IL-1, IL-6, IL-12) and inhibition of CD4+ cells differentiation to Th17 [56]. Moreover, vitamin D 3 stimulates IL-10 production by regulatory T cells (Treg) and proliferation of Treg, which subsequently regulate Th activation and cytokine production, affecting general immunological response [57]. 1,25(OH) 2 D 3 is also speculated to affect B lymphocytes, but this relationship remains controversial. Vitamin D 3 inhibits production of immunoglobulins (IgG and IgM), decreases the proliferation and maturation of memory B cells, and promotes the apoptosis of B cells [58]. Furthermore, B cells also express enzymes concerned in vitamin D 3 metabolism (1α-hydroxylase and 24-hydroxylase), indicating a possible important role of vitamin D 3 in B cell activity [53]. Unfortunately, mature B cells seem to be resistant to 1,25(OH) 2 D 3 influence [58].
Vitamin D 3 also affects the function of phagocytes (macrophages, monocytes). Vitamin D 3 deficiency may manifest by diminished antimicrobial action of monocytes. 1,25(OH) 2 D 3 decreases the expression of toll-like receptor (TLR2 and TLR4), decreases the production of pro-inflammatory molecules like TNF-α, but also stimulates monocytes to differentiate into macrophages, which take part in phagocytosis, chemotaxis and IL-1 production [59,60].
Moreover, vitamin D 3 stimulates leukocytes and some epithelial cells (e.g., oral epithelial, intestines, vagina, keratinocytes) to produce antimicrobial proteins (defensin, cathelicidin). Antimicrobial proteins have strong antibacterial, antifungal and antiviral activity. Mechanisms of action include cell membrane destruction, suppression of microbe protein biosynthesis, and inhibition of nucleic acid biosynthesis or cell division [61].

Role of Vitamin D 3 in Autoimmune Thyroid Diseases
Autoimmune thyroid diseases (AITD), including two main clinical manifestations: Hashimoto thyroiditis (HT) and Graves' disease (GD), represent some of the most common autoimmune diseases, concerning about 5% of the population [12]. AITD are caused by autoimmunization to native antigens, e.g., thyroid stimulating hormone (TSH), thyroid peroxidase (TPO), thyroglobulin (Tg), and TSH-receptor (TSHR). Anti-TPO and anti-Tg are mostly connected with HT, whereas the anti-TSHR (TRAb) is related to GD.
HT is characterized by the lymphocytic infiltration and imbalance between Th1/Th2 lymphocytes [62]. This chronic inflammatory process leads to the destruction of thyroid follicles and is the most common cause of hypothyroidism in the iodine-sufficient population. Within the thyroid, activated Th1 lymphocytes produce TNF-α and INF-γ, which stimulate thyrocytes to secrete CXC10 (C-X-C motif chemokine ligand 10), responsible for the chemotaxis of monocytes, macrophages, T cells, and NK cells, and enhances the autoimmune vicious circle [13].
Having considered the fact that vitamin D 3 plays immune-modulative effect, it may be speculated that vitamin D 3 influences autoimmune inflammation in the thyroid gland in a particular way. Calcitriol affects antigen presenting cells, such as dendritic cells, decreases lymphocyte Th1 activation, and decreases the production of proinflammatory cytokines (IL-2, IL-12, TNF-α). Furthermore, vitamin D 3 suppresses naive T cells differentiation into Th17 lymphocytes, inhibits Th17-connected interleukins secretion (IL-6, IL-17, IL-21, TNF-α), and thus promotes Treg activity and influences Treg/Th17 ratio. Moreover, vitamin D 3 can influence the expression of MHC class II within the thyroid by its downregulation, and consequently limit thyroid autoantigens presentation by APCs to lymphocytes. Additionally, vitamin D 3 decreases maturation and proliferation of B lymphocytes. Therefore, secretion of immunoglobulins IgG and IgM is limited [10,63].
GD is one of the most frequent form of hyperthyroidism in population. Although, the exact cause of GD is still unclear, it is assumed that particular environmental triggers activate proliferation of Treg cells, stimulate maturation of B cells to DCs, and lead to production of thyroid-antibodies. Autoantibodies in GD (TRAb) constantly stimulate TSH-receptors, and subsequently lead to proliferation of thyrocytes and synthesis of thyroid hormones (triiodothyronine, thyroxine), thyroid-specific proteins, and enzymes [64]. Vitamin D 3 inhibits maturation of dendritic cells and inhibits secretion of inflammatory interleukins (IL-2, IL-12, IL-23, TNF-α, INF-γ). Furthermore, vitamin D 3 modulates immune response by a direct influence on Th1 and Th2 lymphocytes, namely by down-regulating Th1 cells activity and up-regulating Th2 cells, as well as Th2-derived cytokines. As mentioned, vitamin D 3 can also reduce proliferation of B lymphocytes and production of immunoglobulins that are associated with GD [10].
The relationship between vitamin D 3 and AITD has been investigated in recent studies. Kivity et al. [65] noticed that vitamin D 3 deficiency was statistically higher in patients with AITD in comparison to healthy individuals (72% versus 30.6%; p < 0.001). What is more, patients with hypothyroidism with AITD and no-AITD were also characterized with lower vitamin D 3 levels (79% versus 52%; p < 0.05). Decreased concentrations of vitamin D 3 appeared to be correlated with increased titer of antithyroid antibodies (p = 0.01). Bozkurt et al. [66] analyzed in their study in total 580 patients, including: newly diagnosed AITD, ongoing AITD and healthy volunteers. The author noticed that the concentration of vitamin 25(OH)D 3 in patients with HT was significantly lower compared to the control group (p < 0.001) and the severity of vitamin D 3 deficiency was corelated with the duration of HT and the titer of TPO and Tg antibodies (p < 0.001). Ma et al. [67] observed lower levels of vitamin D 3 in patients with AITD (HT and GD) and each 5 nmol/L increase in serum 25(OH)D 3 concentrations was associated with a 1.55-and 1.62-fold reduction in GD and HT morbidity. Botelho et al. [68] compared the group of 88 patients with HT with 71 healthy, euthyroid individuals and found an association between vitamin D 3 deficiency and cytokines produced by Th1, Th2 and Th17 cells like TNF-α, IL-5 and IL-17 in patients with AITD. Fang et al. [69] confirmed a positive correlation between antithyroid antibodies, vitamin D 3 deficiency (odds ratio (OR): 2.428, 95% confidence interval (CI): 1.383-4.261), and 25(OH)D 3 inadequacy (OR: 1.198, 95% CO: 0.828-1.733; p = 0.008). The authors also found significantly higher quantities of Th1 and Th17 cells, as well as Th1 and Th17 associated cytokines in HT patients. Chao et al. [70] revealed that the level of 25(OH)D 3 in the HT group was lower than in the non-HT group. The authors noticed a significant difference in thyroid function, namely that the thyroid-stimulating hormone (TSH) levels were significantly higher in both the 25(OH)D 3 insufficiency group as well as the 25(OH)D 3 deficiency group comparing to the 25(OH)D 3 sufficiency group. In addition, the free triiodothyronine (FT 3 ) and thyroxine (FT 4 ) levels were significantly lower in the 25(OH)D 3 insufficiency group. Moreover, the multiple regression analysis showed that HT was significantly correlated with male sex, body mass index (BMI), waist circumference, and TSH [70].
Within the literature, there can also be found a few studies which did not confirm the relationship between AITD and the vitamin D3 deficits. Effraimidis et al. [71] examined 156 participants and did not find association between low vitamin D 3 level and AITD. D'Aurizio et al. [72] analysed 100 patients affected AITD (both HT and GD) and 126 healthy subjects. The authors did not find a significant correlation between vitamin D 3 levels and presence of AITD. Ke et al. [73] observed that, in patients diagnosed with AITD, serum 25(OH)D 3 levels were not associated with thyroid function, presence of antithyroid antibodies, or serum cytokines IL-4, IL-17, and TNF-α. The authors found moderately lower vitamin D 3 levels in HT patients, whereas in GD patients the levels of 25(OH)D 3 were comparable to the values presented within the control group. Ma et al. [67] did not find any significant relationship between serum 25(OH)D 3 level or any of the below listed: titer of anti-TPO, anti-TG, or TSH serum level [67].
Although, there have been mentioned a few manuscripts which did not confirm the relationship between vitamin D 3 and AITD, there are still a lot of publications which state that the relationship between vitamin D 3 with AITD remains indisputable. Further studies are needed to thoroughly evaluate the clinical effects of vitamin D 3 on AITD [74]. Table 1 presents the relationship between vitamin D 3 and AITD on the basis of the literature [65][66][67][68][69][70][71]73].

Vitamin D 3 and Bone Metabolism
Vitamin D 3 plays a prominent role in calcium-phosphate and bone metabolism. The overall feature of vitamin D 3 is to increase and maintain the accurate concertation of calcium and phosphate within the extracellular fluid (ECF). Thus, it creates adequate conditions for proper growth, bone remodeling, as well as mineralization of skeleton [3]. Health bone homeostasis is controlled by the osteoblasts (bone-forming mesenchymal-derived cells) and osteoclasts (bone resorption, multi-nucleus hematopoietic stem-derived cells) [75].
Calcitriol increases the concentrations of calcium and phosphates in ECF through intensified intestinal absorption from nutrients and renal reabsorption from primary urine in proximal tubule. Moreover, it increases the expression of transmembrane glycoprotein Receptor Activator for Nuclear Factor κβ Ligand (RANKL) on osteoblasts. RANKL binds to Receptor Activator for Nuclear Factor κβ (RANK) on preosteoclasts and stimulates their differentiation to mature osteoclasts and accelerates bone resorption [76]. Secondly, 1,25(OH) 2 D 3 stimulates osteoblasts to produce proteins essential in the processes of bone remodeling and mineralization of bone matrix, namely collagen, osteopontin, osteocalcin (dependent on vitamin K bone protein). Moreover, 1,25(OH) 2 D 3 stimulates the activity of alkaline phosphatase, which is essential in the process of bone mineralization [77]. Furthermore, vitamin D 3 promotes bone forming by accelerating the differentiation of monocytes to macrophages, as well as through binding them to the osteoclasts, which enhances bone resorption and calcium release from the bones [78]. Moreover, 1,25(OH) 2 D 3 also plays a significant role in the upregulation of osteoprotegerin (OPG), a soluble glycoprotein, which is a competitive RANKL inhibitor. OPG after being bound to RANKL, inhibits the activation of RANK by its ligand, and subsequently inhibits the processes of osteoclasts activity, maturation and differentiation [79]. Thus, the vitamin D 3 apparently affects bone development, mineralization, and remodeling through its resorption.
Parathormone (PTH) is the one of the most important hormones in bone metabolism. PTH is produced in parathyroid glands. Parathyroid cells, along with renal tubules, brain, heart, skin, stomach, and C cells, express calcium sensing receptors (CaSR), a Class III or Family C G-protein coupled receptor [80]. Serum ionized calcium binds to CaSR and transduces signals through phospholipase C, which hydrolyses phosphatidylinositol 4,5bisphosphonate to diacyl glycerol (DAG) and inositol 1,4,5-triphosphate (IP3). IP3/DAG pathway leads to the degranulation of calcium in endoplasmic reticulum, increased intracellular calcium concentration, and finally blocks degranulation of the vesicles with PTH to the cell membrane. Thus, the secretion of PTH through parathyroids is inhibited [81].
Parathormone activity is strictly corelated with 1,25(OH) 2 D 3 by negative feedback. Increased concentration of calcitriol inhibits CaSR and decreases PTH serum level. Parathormone plays dual role: both anabolic (bone remodeling), and catabolic (bone resorption) ones. On the one hand, pulsating secretion of PTH, through parathyroid receptor type 1 (which belongs to G protein-coupled receptor family), stimulates osteoblasts to produce important compounds for bone matrix composition, namely insulin-like growth factor 1 (IGF-1), fibroblast growth factor (FGF), matrix metalloproteinase (MM-13), or Wnt/βcatenin [82]. Moreover, PTH decreases osteoblasts' apoptosis and intensifies bone matrix formation [83]. On the other hand, PTH indirectly leads to bone resorption through the activation of osteoclasts. PTH downregulates the production of osteoprotegerin, promotes binding RANKL to RANK, and stimulates the differentiation of osteoclasts. Having been activated, osteoclasts produce hydrogen ions, via carbonic anhydrase, to dissolve mineralized matrix into water and ions: calcium, magnesium, phosphates, and other organic substances. Simultaneously, particular hydrolytic enzymes, including cathepsin K and MM-13, are secreted to degrade proteins from bone matrix [84]. During the process of bone resorption, calcium, magnesium and phosphate ions are released to ECF and subsequently to blood circulation. Parathormone also affects kidneys. As mentioned before, it increases the activity of 1α-hydroxylase, and therefore 1,25(OH) 2 D 3 is produced. Furthermore, PTH increases the reabsorption of calcium in renal proximal tubule [85]. To sum up, PTH con-trols the calcium homeostasis within three stages, namely: bone resorption, vitamin D 3 activation, and both intestine and renal calcium absorption.

Vitamin D 3 and Osteoarthritis
Osteoarthritis (OA) is a chronic, degenerative disease involving joint cartilage, synovium, periarticular ligaments, and subchondral bone, affecting up to one in eight adults. It is the most common chronic articular disease. Only a few effective methods of OA treatment have been discussed, but none of them is able to stop or effectively delay the development of the disease [86].
The constantly increasing number of patients diagnosed with OA is associated with increasing life expectancy of population. The cause of the disease is multifactorial, including modifiable and non-modifiable, local and systemic factors. Among the risk factors, there have been mentioned: female sex, race, genetics, old age, type of diet, overweight and obesity, joint injury and mechanical factors, repetitive use of joints, bone density, muscle weakness and joint laxity, low-grade-inflammatory processes, and hormonal system [87,88]. OA can be characterized pathologically, radiographically, and clinically. Diagnosis of OA is not always evident, because some patients with radiological symptoms do not present any clinical manifestation and, at the same time, not everyone with joint symptoms present radiological changes. Therefore, OA should be diagnosed with a diversity of methods, including pathological, clinical, and radiological [89].
The articular cartilage is made of water (>70%) and organic matrix, mostly type II collagen, aggrecan and other proteoglycans [90]. The pathophysiological background of OA involves the whole group of pro-inflammatory cytokines (interleukins IL-1β, IL-6, IL-8), as well as pro-catabolic signalization with nuclear factor kB (NF-kB), mitogen activated protein kinase (MAPK) pathways, and the activation of synovial macrophages and fibroblasts [91]. The inflammatory stimulation of chondrocytes results in upregulation of proteinases, especially aggrecanase and collagenase. The main enzymes responsible for degradation of cartilage matrix are A Disintegrin and Metalloproteinase with Thrombospondin motifs (ADAMTS) and zinc-dependent metalloproteinases (MMPs) belonging to the MMP families. The MMPs group includes collagenases MMP-1, MMP-13 (type II collagen proteinase), and MMP-3 (effective aggrecanase) [92]. The additive effect of pro-inflammatory mediators, mechanical injuries, and oxidative stress affect the function and vitality of chondrocytes, resulting in further degeneration of cartilage and bone underneath.
Recent studies suggest that vitamin D 3 may play a significant role in osteoarthritis. Several studies revealed that chondrocytes express VDR. Orfanidou et al. [93] showed increased expression of VDR in the areas of cartilage erosion in OA. In a prospective study with 418 participants with already diagnosed OA Zhang et al. [94] found that participants with both decreased concentration vitamin D 3 and high concentration of PTH had a more than three-fold increased risk of OA progression. Heidari et al. [95] presented similar conclusions, however the significant difference was observed in the younger group of patients (<55 years, p = 0.01), whereas in patients aged more than 60 years old the association between serum 25(OH)D 3 deficiency and OA was not statistically significant. In another, two-year prospective study with 413 enrolled participants with knee OA and low 25(OH)D 3 serum level, Jin X et al. [96] revealed that treatment with 50 000 IU of vitamin D 3 monthly did not result in significant changes in MRI-measured tibial cartilage volume or WOMAC (Western Ontario and McMaster Universities Osteoarthritis Index) knee pain score. Contrary to this, Gao XR et al. [97] found that daily supplementation of more than 2000 IU of vitamin D 3 significantly decreased pain and improved function of the joint on the basis of the WOMAC scale. However, the authors did not find any beneficial effect of vitamin D 3 supplementation on the prevention of tibial cartilage loss. What is more, Divjak et al. [98] administrated 4000 IU of 25(OH)D 3 daily to patients with primary knee OA and compared the cytokine profile before and after intervention. The authors observed that as the concentration of IL-1β (p < 0.01), IL-23 (p < 0.01), and IL-33 (p < 0.01) significantly increased, the concentration of TNF-α (p < 0.01), IL-13 (p < 0.01), and IL-17 (p < 0.01) significantly decreased, whereas the concentration of IL-4 did not change significantly. The prescribed treatment with vitamin D 3 appeared to reduce joint pain, joint stiffness, and to improve physical function. The authors suggested that vitamin D 3 supplementation may be recommended as a new co-therapeutic treatment in the course of knee OA.
Vitamin D 3 is also known to affect bone regeneration, bone malformation, as well as osseointegration of implants. There have been published several metanalyses and systematic reviews regarding the relationship between vitamin D 3 and abovementioned processes [99][100][101]. Salomó-Coll et al. [102] performed an animal study and noticed reduced crestal bone loss as well as increased osteointegration by 10% around implants supplemented with vitamin D. Dvorak et al. [103] described that vitamin D deficiency negatively affected implants osseointegration in rats. Werny et al. [100] stated that 75% of the analyzed studies had confirmed the positive effect of vitamin D supplementation on bone regeneration. Unfortunately, most of the abovementioned studies were performed on animals. So far, several studies have been performed on human patients, but the results are often contradictory. Kwiatek et al. [104] showed, in a prospective, randomized clinical trial on a group of 122 patients, that vitamin D supplementation and treatment of vitamin D deficiency led to an increased bone level surrounding the implant 12 weeks after surgery. Contrary to this study, Grønborg et al. [105] performed a randomized double-blinded placebo-controlled trial with 143 women diagnosed with vitamin D deficiency who received special diet reach in vitamin D. After 12 weeks the author noticed a statistically significant increase in vitamin D serum concentration (p < 0.05). However, they did not notice significant changes in bone turnover biomarkers, nor improvement in muscle strength. Having considered all of the above mentioned, further randomized human studies are necessary to establish the role of vitamin D 3 in the process of implant osseointegration.
Undoubtedly, vitamin D 3 affects the metabolism of bone and chondrocytes by the modulation of pro-and anti-inflammatory responses. However, there are no specific guidelines regarding the use of vitamin D 3 in the treatment of OA. In light of the latest research, the use of vitamin D 3 in patients diagnosed with OA seems to be promising. Table 2 presents the relationship between vitamin D 3 and OA on the basis of the literature [93][94][95][96]98].

Vitamin D 3 and Temporomandibular Joint Osteoarthritis
Temporomandibular disorders (TMD) is an umbrella term describing the pathology within the temporomandibular joints and/or adjacent muscles [106]. The most typical symptoms for TMD include: pain in the area of TMJs, limited mouth opening, and noises within the TMJs [106]. The etiology of TMD is multifactorial and encompasses several different items, which may be allocated into one of the subgroups, namely: host-adaptive capacity factors (genetics, age, estrogens, systemic diseases, abnormal remodeling of subchondral bone) and mechanical factors (excessive mechanical stress, parafunctions, functional overloading, microtrauma) [107,108]. In the past, it was believed that occlusion played a major role in the development of TMD [109,110]. However, according to the most recent research, there is not enough evidence to confirm that occlusion may lead to TMD [111][112][113]. TMD is a complex condition, modified by many factors, and which often binds with many diseases [114,115].
Because of the fact that TMD is not a dental, but an interdisciplinary issue, the treatment of TMD, including temporomandibular joint osteoarthritis (TMJ OA), requires the cooperation of different specialists, including physiotherapists, dentists, rheumatologists, endocrinologists, laryngologists, maxillofacial surgeons, psychiatrists, psychologists, and speech therapists.
TMJ OA is a degenerative joint disease (DJD). According to the Diagnostic Criteria for Temporomandibular Disorders (DC/TMD), to diagnose DJD, it is necessary to meet the following criteria: noises within the TMJ that occur during the movement of the mandible within the last 30 days or noise within the TMJ which is reported by the patient during the examination [116]. Moreover, it is necessary to detect the crepitus with palpation during mandibular movement [116]. Nonetheless, the diagnosis based only on anamnesis and clinical examination, without imaging, is characterized by sensitivity of 0.55 and specificity of 0.61 [116]. Radiological symptoms typical for DJD are: erosion, osteophytes, generalized sclerosis, and subchondral cysts. According to the DC/TMD, articular surface flattening and cortical sclerosis are regarded as indeterminant findings for DJD [116].
As previously stated, vitamin D 3 plays a significant role in calcium-phosphate and bone metabolism [3,75]. It was also reported that vitamin D 3 deficits may be correlated with the development and progression of osteoarthritis [93,94]. Although it may be speculated that low serum concentration of vitamin D 3 is correlated with the development and/or progression of TMJ OA, so far there have been published only few studies regarding this topic and the results remain inconsistent.
Shen et al. [117] examined 25(OH)D 3 1α-hydroxylase knockout mice which had been fed a rescue diet. The authors found that 1,25(OH) 2 D 3 deficient mice presented reduced bone mineral density and reduced subchondral bone volume within the mandibular condyles. Shen et al. [117] also reported that 1,25(OH) 2 D 3 deficiency was associated with the changes in the shape of articular surfaces, as well as in the thickness of articular cartilage. The authors observed articular surface erosion in 1,25(OH) 2 D 3 deficient mice. Shen et al. [117] concluded that 1,25(OH) 2 D 3 deficiency was correlated with erosive TMJ OA phenotype, increased DNA damage, cellular senescence, as well as with the production of inflammatory cytokines associated with senescence.
Hong et al. [118] noticed that 1,25(OH) 2 D 3 was significantly correlated with TMJ OA, both development and progression, in young and postmenopausal women. The authors indicated that vitamin D 3 could be considered a therapeutic agent for TMJ OA. Jagur et al. [119] indicated that decreasing bone mineral density as well as low serum concentration of 25(OH)D 3 may be considered predictors of bone destruction in the area of TMJs. Gupta et al. [120] found that in patients diagnosed with TMD, who were also vitamin D 3 deficient, supplementation of vitamin D 3 in addition to stabilization splint therapy led to quicker alleviation of pain in the area of TMJs. Demir et al. [121] compared healthy individuals and patients with TMD. The authors did not find statistically significant differences between the examined groups regarding the serum concentration of: calcium, magnesium, phosphorus, calcitonin, and 25(OH)D 3 . Patients diagnosed with TMD presented significantly increased concentration of parathyroid hormone. According to Demir et al. [121], vitamin D 3 deficiency in patients diagnosed with TMD requires assessment and correction. Madani et al. [122] performed a case-control study and found that there were no statistically significant differences in the serum concentrations of: alkaline phosphatase, phosphate, calcium, PTH, and vitamin D 3 between patients diagnosed with TMD and healthy individuals.
To sum up, it may be speculated that vitamin D 3 concentrations may be different in various TMDs, which may consequently be the cause of inconsistency in the obtained results from the above presented research. Studies in which only cases with TMJ OA were included clearly indicated that 1,25(OH) 2 D 3 was significantly correlated with TMJ OA [110,111]. Kui et al. [123] concluded that further studies regarding the relationship between vitamin D 3 concentration and TMDs are absolutely needed and that supplementation of vitamin D 3 is recommended for vitamin D 3 deficient patients who suffer from TMD.

Conclusions
Calcitriol impresses a pleiotropic effect on the human biology and metabolism. Its modulative function upon the immune system is based on the reduction of Th1 cell activity and increased immunotolerance. Severe vitamin D 3 deficiency may lead to an imbalance in relationship between Th1/Th17 and Th2, Th17/Th reg, and is considered by some authors as one of the possible backgrounds of autoimmune thyroid diseases (AITD), e.g., Hashimoto's thyroiditis or Graves' disease. Moreover, vitamin D 3 , through a direct and indirect influence on bones and joints, may also play an important role in the development and progression of degenerative joint diseases, including temporomandibular joint osteoarthritis. Further randomized, double blind studies are needed to unequivocally confirm the relationship between vitamin D 3 and abovementioned diseases and to answer the question concerning whether vitamin D 3 supplementation may be used in the prevention and/or treatment of either AITD or OA diseases.